Nephrotic syndrome is a common clinical type of glomerular diseases in the elderly and has its own characteristics in the pathological types, clinical manifestations, and diagnoses. Renal biopsy is an important diagnostic method for elderly patients with nephrotic syndrome. Membranous nephropathy is the most common primary pathology while amyloidosis and diabetic nephropathy are common secondary causes. Individualized treatments should be performed according to ages and physical characteristics of the elderly patients.

Nephrotic syndrome is a group of clinical syndromes mainly characterized as follows. The serum albumin is ≤30 g/L, the urine protein quantitation is more than or equal to 3.5 g in 24 h. Edema and elevated blood lipid are its main symptoms. It is a common clinical type of elderly glomerular disease. Data from abroad indicate that nephrotic syndrome takes up 12-61.5% [1] in all renal biopsy patients with elderly glomerular diseases. Among elderly renal biopsy patients more than 80 years old, nephrotic syndrome takes up 13.2-50.7%, [2],[3] and the corresponding proportion is 59.53% [4] in domestic renal biopsy patients more than 65 years old. Compared with young people, elderly nephrotic syndrome has many basic diseases and complications, and it is hard to treat for the effects of senility and various diseases. Although the clinical manifestations of elderly nephrotic syndrome patients are the same, the pathological types are diverse and the prognoses are also different. Hence, clinical practice and pathological examination need to be closely integrated to make comprehensive analysis and accurate judgment and improve patients' prognosis.

Pathological Type

First, secondary cause should be excluded in elderly nephrotic syndrome. According to the analyses abroad, the main pathological types of secondary nephrotic syndrome are diabetic nephropathy and amyloidosis, [3] which is consistent with the researches in China, respectively accounting for 10.66% and 1.64% [5] in elderly nephrotic syndrome, all with higher morbidity than nonelderly patients. The most common reason of renal amyloidosis is immunoglobulin-related amyloidosis, taking up 85.9% of all renal amyloidosis patients. Renal amyloidosis is often secondary to plasma cell disease and multiple myeloma. AA type amyloidosis is posted in the second place, approximately taking up 7% and mainly related to arthritis deformans and chronic infectious diseases. Amyloidogenic leukocyte chemotactic factor 2 takes up 2.7% [6] and is listed in the third place. Making clear of the main ingredients of amyloid substance is significant to formulate a treatment plan and judge prognosis and kidney deposition.

Although diabetic nephropathy occupies large proportion in secondary elderly nephrotic syndrome, not all diabetic patients' nephrotic syndrome is caused by diabetic nephropathy. Diabetes can combine membranous nephropathy, minimal change disease and other primary nephrotic syndromes. [7] If the patient keeps acute renal failure, hematuria, short time diabetes, yet without diabetic retinopathy, it is probably not diabetic nephropathy.

There are a variety of pathological types of the primary elderly nephrotic syndrome, but the main types are membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis according to the data from abroad. [3] Data in China also report that membranous nephropathy is the most common pathological type of elderly nephrotic syndrome (56.7%), and the second one is minimal change disease (9.02%). [5] As the most common elderly glomerular lesion, membranous nephropathy takes up 56.97% among all nephrotic syndromes, and about 10% membranous nephropathies often appear after neoplastic disease. [8] There is also a report indicates that about 40-45% patients find nephrotic syndrome manifestations first before tumor. [9] Some researches show the morbidity of tumor associated membranous nephropathies takes up 9.4% [10] among patients more than 60 years old, and the proportion is 24.7% [11] among patients more than 64 years old. The common tumors include intestine, lung, stomach, pancreas, kidney, prostate, and skin tumors. For patients more than 65 years old with a smoking history, lung cancer is the most common one. [12] Membranous nephropathy may be caused by a tumor, immunosuppressant or both at the same time. [13]

In addition, in elderly renal biopsy tissue, global or focal glomerulosclerosis, focal renal tubular atrophy, and lumen expansion can be found, with diverticulum and cyst. At the same time, some pathology changes such as renal interstitial fibrosis and hyalinization of the renal artery will take place. When it comes to renal pathology diagnosis, attention should be paid to its cause. You will find the pathological changes are caused by aging-related degenerative changes or characteristic lesions.

Clinical Manifestations and Complications

Clinical manifestations

Often caused by eyelid or lower limb edema, bed patients may also suffer from lumbar sacral edema, and the severe symptoms include pleural effusion, peritoneal effusion, and pericardial effusion. Proteinuria can be found through a urine test, with or without red blood cells, and the urinary protein quantitation is more than or equal to 3.5 g within 24 h, being selective or nonselective. For amyloid light type amyloidosis patients, the immunoglobulin increases, the light chain proportion inverses, and the paraproteinemia will appear through a blood test. The decrease of serum albumin is related to the amount of proteinuria, but not entirely parallel. Other plasma proteins, such as immune globulin, complement, coagulation, fibrinolysis related proteins, and binding protein, will also change. Elderly nephrotic syndrome patients are often combined with hypertension, diabetes, cerebrovascular disease, coronary disease, and other basic diseases with corresponding clinical manifestations.

Complications

Acute renal failure

For the decline of physiological function, elderly people's kidney function will decrease, besides, renal interstitial edema, and renal tubular interstitial damage will take on. Patients have poor tolerance to capacity loss and keep the high incidence of acute renal failure. If the patients cannot get timely and effective treatment, it may threat to their lives. The most common pathological type of acute renal failure is focal segmental sclerosis, and the second are minimal change disease and membranous nephropathy. In addition, vasculitis has high morbidity in elderly people and may be the cause of acute renal failure. [5] Acute renal failure is also an important indication of renal biopsy.

Infection

Due to the loss of immune globulin and decreased function of white blood cell, nephrotic syndrome patients are easily to be infected. Besides, for different degrees of senility in organs, elderly people's systemic immune response ability will decrease. Hence, they suffer from the high risk of infection. Moreover, the application of steriod and immunosuppressant further restrains immune function in the body, leading to increased infection incidence for elderly nephrotic syndrome patients, even threatening their lives.

Thrombosis and embolism

Nephrotic syndrome is easy to form thrombus due to blood concentration, increasing blood viscosity and red cell aggregation, synthetic increase of coagulation factor V and VIII for the loss of urinary protein, decreased plasminogen, anti-thrombin III, and the disorder of triglyceride of high-grade, coagulation and anti-coagulation mechanisms. Moreover, for the reduced activities, it is also easy to form a thrombus. Age is an important risk factor for thrombosis. Most of the thrombembolia occurs 6 months [14] after the diagnosis of the nephrotic syndrome. The most common pathological type of thrombembolia is membranous nephropathy. [15] Patients who need renal biopsy should stop taking Aspirin and other anticoagulant drugs, and they should stay in bed after renal biopsy, therefore, the possibility of lower extremity venous thrombosis will increase.

Others

Nephrotic syndrome can cause protein-energy wasting for albumin loss, decreased appetite, renal inadequacy, acidosis and the use of glucocorticoid, which will increase infection and mortality rate. The common performances are hypocalcemia, deficiency of trace elements copper, zinc, iron, etc. Elderly people's renal sodium retention function is decreasing obviously. Long-term low salt diet and the application of diuretics may cause hyponatremia and low potassium.

Diagnosis

The clinical manifestation is edema. Urine protein quantitation is more than or equal to 3.5 g in 24 h, and serum albumin is ≤30 g/L. The diagnosis is not difficult, but elderly nephrotic syndrome's diagnosis includes pathological diagnosis. Old age is not the contraindication of renal biopsy. Renal biopsy is significant to confirm pathological types, treatment plan, prognosis and secondary factors. [16] For elderly people, although the renal biopsy is more difficult than younger people for their poor health, decreased reactivity in the process of puncture and cooperation ability with doctors, the incidence rate of severe complications is not higher than young people if the preoperative preparation is fully done, and the doctor operates skillfully, fast, and accurately. [5]

Patients are always combined with intestinal mucosal edema and ascites, so their digestive ability is poor. Give them food that is easy to digest, mainly bland diet. Due to decreased serum albumin, patients are in the negative nitrogen balance. For non-chronic renal failure nephrotic syndrome, the dose of protein intake is 1.0-1.5 g/(kg/day). If patients have entered to chronic renal failure stage, the protein intake should be appropriately reduced. Hyperlipemia will promote the occurrence of atherosclerosis and coronary heart disease and the formation of thrombosis and embolism. Hence, the low-fat diet should be given to patients with high blood lipids. Usually, the lipid is <30% among total calories.

Edema treatment

To elderly patients, edema-reducing treatment should be kept in slow progress. Large dose of diuretics may bring about the risk of thrombosis, hypotension, and increasing protein loss. By supplying albumin and moderate diuretic, most patients' edema and serous cavity effusion will be eased. For patients with large amount of serous cavity effusion, they can take puncture and drainage therapy if they have the symptoms of chest tightness, shortness of breath and abdominal distension, etc.

Steroid and immunosuppressant treatment

Steroid usage can cause infection, elevated blood pressure, osteoporosis, femoral head necrosis, gastrointestinal ulcers, and other side reactions. Immunosuppressant will induce a tumor, severe hepatic lesion, hematopoietic disorder and water electrolyte disorder. Hence, it is necessary to fully assess patients' conditions and exclude tumor when using steroid and immunosuppressant. Therefore, patients' conditions should be closely monitored in the process of treatment. Moreover, the dose of steroid and immunosuppressant should be reduced as far as possible to avoid the occurrence of complications.

Elderly minimal change diseases are sensitive to steroid, so the steroid dose had better refer to children's treatment experience. In general, the initial dose of prednisone is 0.8-1.0 mg/(kg/day), totally no more than 60 mg/day. Moreover the dose should be slowly reduced after 8 weeks. Due to the slow effect of the medicine, adult patients' initial treatment needs to be extended to 12 weeks. However, the elderly have small recurrence rate. For focal segmental glomerular sclerosis patients with nephrotic syndrome, simple steroid therapy is limited and works slowly. Partial and complete remission rates are only from 15% to 40%, and the median complete remission time is 3-4 months. For steroid dependence or recurrent patients, they need to add immunosuppressant, such as cyclophosphamide, cyclosporine, tacrolimus, or mycophenolate. Moreover, it is also reported that rituximab and adalimumab can be used in focal segmental glomerular sclerosis treatment. [17] For membranous nephropathy, different treatment plans should be taken according to different risk classifications. For example, if the urine protein quantitation is ≤4 g within 24 h and the renal function is normal, it belongs to low risk and should be given renin-angiotensin system (RAS) blocker therapy; If the urine protein quantitation is 4-6 g or 6-8 g within 24 h, more than 6 months, and the renal function is normal, immunosuppressant combined with steroid therapy can be taken. For membranous nephropathy, it is not very effective only through steroid therapy. Steroid combined with cytoxan belongs to the first-line drug. If the condition is not relieved, steroid combined with cyclosporine therapy should be considered. Cyclosporine is normally used in patients with normal renal function. Elderly patients often take many basic drugs, which may affect the blood concentration of cyclosporine and other immunosuppressant. Hence, timely monitoring is necessary.

Complication treatment

Osteonecrosis of the Femeral Head (ONFH) is the severe side effect caused by steroid, which seriously affects elderly patients' quality of life. However, at present, there is no preventive method, so early detection and intervention is necessary. If patients feels pain in groin or hip and spreads to thigh (or one side gonyalgia and coxalgia after activity) and suffer from slowly progressive increase, they should realize the possibility of ONFH and take nuclear magnetic resonance.

As to the osteoporosis caused by steroid, for postmenopausal women or the men more than 50 years old, treatment guideline suggests taking steroid more than 7.5 mg/day. If fracture risk assessment tool assessment indicates the bone loss belongs to low risk, osteoporosis prevention treatment should be taken. The exercise quantity of the elderly is decreasing and they keep fragile bone, so they need to increase physical exercise. Besides, Vitamin D and diphosphonate can reduce bone loss. [18]

Patients once had peptic ulcer could use gastric mucosa protection drugs before steroid therapy, steroid therapy could induce peptic ulcer.

The key to acute renal injury prevention and treatment is implementing early diagnosis and treatment plan. Early treatment means taking a renal biopsy as soon as possible to get pathological diagnosis and guide treatment. Minimal change disease and crescent nephritis are sensitive to steroid, so steroid treatment should be immediately taken to ease the illness, increase urine volume and make renal function gradually return to normal standard. To avoid excessive diuretic, RAS blocker may reduce the occurrence of the acute renal failure. For dialysis, most patients do not need hemodialysis. However, in the conditions of high serum creatinine, severe water, electrolyte and acid-base balance disorder, dialysis is necessary to support treatment and help patients get through oliguria stage safely. If the condition permits, continuous blood purification treatment should be conducted to control volume accurately and maintain the steady state of hemodynamics.

Actively prevent and treat thrombembolia: There are no large-scale prospective randomized researches about the effectiveness and safety of thrombembolia prevention and treatment.

Preventive treatment not only needs to effectively prevent thrombosis, but it cannot increase the bleeding risk of the originally nonthrombosis formed patients. Elderly patients need more comprehensive assessments of thromboembolism risk. If patients' serum albumin is <20 g/L, with basic diseases such as lupus nephritis and membranous nephropathy, low molecular heparin preventive treatment is recommended to long-term rest patients. Some studies indicate statins can decrease nephrotic syndrome related thrombembolia risk. [19] Some oral and anticoagulant drugs, such as rivaroxaban and dabigatran, can prevent the formation of thrombus for surgical or atrial fibrillation patients. But there are no relevant application researches in patients with nephrotic syndrome. Once a thrombus has been formed, low molecular heparin subcutaneous injection should be given. Furthermore, it can be combined with warfarin with international normalized ratio. The treatment period is 3-6 months. [15]

Antihypertensive and lipid-lowering treatment

RAS blocker has a renal protective function, not relying on anti-hypertensive effect, and becomes the first-line antihypertensive drug of chronic kidney disease. Notice, observe whether patients have a serious shortage of effective circulating blood volume or not. For patients accompanied by atherosclerosis, hypertension, hyperlipemia, coronary disease and mellitus, and renal artery ultrasonography had better be conducted to exclude simultaneous renal artery stenosis which can induce or aggravate acute renal failure. Active lipid-lowering therapy should be given to elderly nephrotic syndrome patients to prevent cardiovascular diseases and decrease the occurrence thrombus. The selective drug is HMC CoA reducase inhibitor.

Elderly nephrotic syndrome has its manifestations and pathological types related to corresponding age. Renal biopsy is the important means to diagnose the elderly nephrotic syndrome. As to treatment, clinical guideline should be followed, and individualized treatment plan should also be implemented according to patients' age and physical features. The majority of patients with primary nephrotic syndrome will get the better curative effect by choosing suitable steroid and immunosuppressant, immediate treatment, and appropriate measures. However, secondary nephrotic syndrome, like diabetic nephropathy and amyloidosis, has a poor prognosis.